Molecular alterations in indolent, aggressive and recurrent ovarian low‐grade serous carcinoma

McIntyre, John B.; Rambau, Peter; Chan, Angela; Yap, Sidney; Morris, Don; Nelson, Gregg; Köbel, Martin

doi:10.1111/his.13071

Cited by 29 publications

(27 citation statements)

References 33 publications

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“…Additionally, RAS mutations were often associated with RAS copy number gain. As previously reported [24, 46, 50] we also detected multiple and distinct genomic alterations affecting other genes related to the MAPK cell signaling pathway. It is worth noting that the individual comparison of genomic profiles between LGSC cultures showed substantial variations in the types of gene mutations and copy-number alterations, indicating widespread molecular differences in LGSC tumors between patients.…”

Section: Discussionsupporting

confidence: 85%

Markers of MEK inhibitor resistance in low-grade serous ovarian cancer: EGFR is a potential therapeutic target

et al. 2019

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BackgroundAlthough low-grade serous ovarian cancer (LGSC) is rare, case-fatality rates are high as most patients present with advanced disease and current cytotoxic therapies are not overly effective. Recognizing that these cancers may be driven by MAPK pathway activation, MEK inhibitors (MEKi) are being tested in clinical trials. LGSC respond to MEKi only in a subgroup of patients, so predictive biomarkers and better therapies will be needed.MethodsWe evaluated a number of patient-derived LGSC cell lines, previously classified according to their MEKi sensitivity. Two cell lines were genomically compared against their matching tumors samples. MEKi-sensitive and MEKi-resistant lines were compared using whole exome sequencing and reverse phase protein array. Two treatment combinations targeting MEKi resistance markers were also evaluated using cell proliferation, cell viability, cell signaling, and drug synergism assays.ResultsLow-grade serous ovarian cancer cell lines recapitulated the genomic aberrations from their matching tumor samples. We identified three potential predictive biomarkers that distinguish MEKi sensitive and resistant lines: KRAS mutation status, and EGFR and PKC-alpha protein expression. The biomarkers were validated in three newly developed LGSC cell lines. Sub-lethal combination of MEK and EGFR inhibition showed drug synergy and caused complete cell death in two of four MEKi-resistant cell lines tested.ConclusionsKRAS mutations and the protein expression of EGFR and PKC-alpha should be evaluated as predictive biomarkers in patients with LGSC treated with MEKi. Combination therapy using a MEKi with EGFR inhibition may represent a promising new therapy for patients with MEKi-resistant LGSC.Electronic supplementary materialThe online version of this article (10.1186/s12935-019-0725-1) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 85%

Markers of MEK inhibitor resistance in low-grade serous ovarian cancer: EGFR is a potential therapeutic target

et al. 2019

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“…More recently, NRAS mutations were described in LGSOC. Five studies identified 12 NRAS mutations (either at Q61R or Q61K) in a total of 118 cases, resulting in an average frequency of 9.3% [7], [9], [26], [27], [28]. We found three NRAS mutations in our series.…”

Section: Discussionmentioning

confidence: 46%

Loss of 1p36.33 Frequent in Low-Grade Serous Ovarian Cancer

et al. 2019

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BACKGROUND: Low-grade serous ovarian cancer (LGSOC) is a rare subtype of epithelial ovarian carcinoma. Limited data regarding the molecular-genetic background exist beyond mutations in the RAS signaling pathway. There is a growing need to better characterize these tumors due to chemoresistance and limited therapeutic options in advanced or recurrent disease. METHODS: We performed genome-wide copy number aberration (CNA) profiles and mutation hotspot screening ( KRAS, BRAF, NRAS, ERBB2, PIK3CA, TP53 ) in 38 LGSOC tumor samples. RESULTS: We detected mutations in the RAS-signaling pathway in 36.8% of cases, including seven KRAS , four BRAF , and three NRAS mutations. We identified two mutations in PIK3CA and one mutation in MAP3K1, EGFR , and TP53 . CNAs were detected in 86.5% of cases. None of the focal aberrations was correlated with specific clinical characteristics. The most frequently detected CNA was loss of 1p36.33 in 54.1% of cases, with a trend towards lower progression-free survival and overall survival in patients with 1p36.33 loss. CONCLUSIONS: Activating RAS mutations were dominant in our series, with supplementary detection of two PIK3CA mutations which may lead to therapeutic options. Furthermore, we detected 1p36.33 deletions in half of the cases, indicating a role in tumorigenesis, and these deletions may serve as a prognostic marker.

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“…We have previously shown that progesterone receptor (PGR) expression is a favorable prognostic factor in LGSC . Perhaps PGR and p16 status could help to stratify LGSC regarding prognosis . Another consideration is the possible predictive utility of absent p16 expression for CDK4 inhibitors as suggested in clinical trials for breast and other cancers .…”

Section: Discussionmentioning

confidence: 99%

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

Rambau

Vierkant

Intermaggio

et al. 2018

The Journal of Pathology CR

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We aimed to validate the prognostic association of p16 expression in ovarian high‐grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical‐grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis‐associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47–2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30–2.75, p = 0.004), while absence was associated with shorter OS in low‐grade serous carcinomas (HR: 2.95, 95% CI 1.61–5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype‐specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low‐grade serous carcinoma justifies CDK4 inhibition.

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Molecular alterations in indolent, aggressive and recurrent ovarian low‐grade serous carcinoma

Abstract: Despite limited case numbers, it appears that current molecular testing is inferior to a pathological parameter or protein expression in predicting the outcome of LGSCs. Prediction of outcome based on the primary tumour may be confounded by additional changes acquired over time.

Cited by 29 publications

References 33 publications

Markers of MEK inhibitor resistance in low-grade serous ovarian cancer: EGFR is a potential therapeutic target

Markers of MEK inhibitor resistance in low-grade serous ovarian cancer: EGFR is a potential therapeutic target

Loss of 1p36.33 Frequent in Low-Grade Serous Ovarian Cancer

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

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